Questioning aerosol transmission of influenza.

To the Editor: We have reviewed the literature cited in Tellier's Review of Aerosol Transmission of Influenza A Virus (1) and disagree that it supports the conclusions drawn regarding the importance of aerosols in natural influenza infection. In certain cited studies, researchers recovered viable virus from artificially generated aerosols; this is not evidence that aerosol transmission leads to natural human infection (2,3). By standard definitions, the rarity of long-range infections supports the conclusion that effective aerosol transmission is absent in the natural state (4) (www.cdc.gov/neidod/dhqp/gl_isolation_hicpac.html). The superior efficacy of inhaled versus intranasal zanamivir is referenced as support for the idea that the lower respiratory tract is the preferred site of influenza infection; however, 1 study cited is insufficiently powered, and the other 2 do not compare the intranasal and inhaled routes (5-7). The major site of deposition of inhaled zanamivir is the oropharynx (77.6%), not the lungs (13.2%) (www.gsk.ca/en/products/prescription/relenza_m.pdf). In another flawed study (8), study participants naturally infected with wild-type virus are compared with study participants experimentally infected with an attenuated strain.

In a review of such relevance, critical analysis of confounding factors is necessary. The Alaska Airlines outbreak (9) is presented as proof of airborne influenza transmission; however, droplet/contact transmission remains plausible because passenger movement was not restricted and the index patient was seated in high-traffic area. In the Livermore Hospital study (10), serious confounders such as bed arrangements, number of influenza exposures, patient mix, and ventilation were not accounted for.

We encourage readers of Teller's article to review the relevant primary literature. We believe that the only reasonable conclusion that can be drawn at this time is that aerosol transmission does not play a major role in natural influenza epidemiology. Whether aerosols play any role in the transmission of influenza is a question demanding an answer; it is clear that we do not yet have that answer.

(1) Currently affiliation: Durham Region Health Department, Whitby, Ontario, Canada

References

(1.)Tellier R. Review of aerosol transmission of influenza A virus. Emerg Infect Dis. 2006;12:1657-62.

(2.)Hemmes JH, Winkler K, Kool SM. Virus survival as a seasonal factor in influenza and poliomyelitis. Antonie Van Leeuwenhoek. 1962;28:221-33.

(3.) Loosli C, Lemon H, Robertson O, Appel E. Experimental air-borne influenza infection. 1. Influence of humidity on survival of virus in air. Proc Soc Exp Biol Med. 1943;53:205-6.

(4.) Health Canada. Routine practices and additional precautions for preventing the transmission of infection in health care: revision of isolation and precaution techniques. Canadian Communicable Disease Report. 1999;25(Supp14).

(5.) Calfee DE Peng AW, Cass LM, Lobo M, Hayden FG. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimierob Agents Chemother. 1999;43:1616-20.

(6.) Kaiser L, Henry D, Flack NP, Keene O, Hayden FG. Short-term treatment with zanamivir to prevent influenza: results of a placebo-controlled study. Clin Infect Dis. 2000;30:587-9.

(7.) Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med. 2000;343:1282-9.

(8.) Little JW, Douglas RGJ, Hall WJ, Roth FK. Attenuated influenza produced by experimental intranasal inoculation. J Med Virol. 1979;3:177-88.

(9.) Moser MR, Bender TR, Margolis HS, Noble GR, Kendal AP, Ritter DG. An outbreak of influenza on a commercial airliner. Am J Epidemiol. 1979;110:1-6.

(10.) McLean RL. The effect of ultraviolet radiation upon the transmission of epidemic influenza in long-term hospital patients. Am Rev Respir Dis. 1961;83:36-8.

In response: Coughing and sneezing during influenza produce virus-containing aerosols. In the laboratory, influenza virus in homogeneous aerosols, flee of large droplets, can infect volunteers at very small doses; studies of infectivity decay in aerosols show persistence for hours. These observations required the generation of artificial aerosols but were performed under conditions that do not enhance stability or virulence (1,2). Therefore, they have great relevance for natural infections.

The scarcity of infections that are transmitted long range in well-ventilated areas does not rule out infectivity of aerosol-size particles near patients. That only 13% of inhaled zanamivir is deposited in the lungs is not important: after inhalation, the zanamivir concentration throughout the respiratory tract is >10 [micro]mol/L, orders of magnitude above the 50% inhibitory concentration (3). Intranasal zanamivir is protective against large droplets (4), which are trapped in the nose (5). The requirement for inhaled zanamivir in natural infections (6,7) points to aerosol contribution and to the lower respiratory tract as the preferred site.

Little et al. (8) compared the severity of natural illness caused by H3N2 strains from 1974 and 1975 to that caused by experimental intranasal inoculation from H3N2 strains from 1972, 1974, and 1975. The challenge strains underwent few passages; characterizing them as "attenuated" is incorrect.

Although large droplets probably accounted for some cases in the Alaska Airlines outbreak (9), this outbreak was remarkable for its high attack rate (72%) and for deficient ventilation, which would increase transmission by aerosols but not by large droplets. Passengers with influenza are common, yet with proper ventilation such an attack rate is uncommon.

During the Livermore Hospital study (10), respiratory infections other than influenza occurred in both groups. It was assumed that visitors and staff would provide equivalent introductions of the virus during the several months of the study; 4 study participants in the irradiated building seroconverted, but the virus did not propagate. The concern by Lemieux and colleagues about ventilation is odd because it would affect mostly aerosol transmission.

I concur with encouraging readers to review the original references. They make a compelling case for the importance of aerosol transmission. In contrast, no convincing data rule it out.

Raymond Tellier *

* Hospital for Sick Children, University of Toronto, Toronto, Canada

References

(1.) Douglas RG. Influenza in man. In: Kilbourue ED, editor. The influenza viruses and influenza. New York: Academic Press; 1975. p. 375-447.

(2.) Schaffer FL, Soergel ME, Straube DC. Survival of airborne influenza virus: effects of propagating host, relative humidity, and composition of spray fluids. Arch Virol. 1976;51:263-73.

(3.) Cass LM, Brown J, Pickford M, Fayinka S, Newman SP, Johansson CJ, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinet. 1999;36(Suppl 1):21-31.

(4.) Calfee DP, Peng AW, Hussey EK, Lobo M, Hayden FG. Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection. Antivir Ther. 1999;4:143-9.

(5.) Knight V. Airborne transmission and pulmonary deposition of respiratory viruses. In: Hers JF, Winkles KC, editors. Airborne transmission and airborne infections VIth International Symposium on Aerobiology. New York: Wiley; 1973. p. 175-82.

(6.) Kaiser L, Henry D, Flack NP, Keene O, Hayden FG Short-term treatment with zanamivir to prevent influenza: results of a placebo-controlled study. Clin Infect Dis. 2000;30:587-9.

(7.) Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot M J, Hammond JM, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med. 2000;343: 1282-9.

(8.) Little JW, Douglas RG Jr, Hall W J, Roth FK. Attenuated influenza produced by experimental intranasal inoculation. J Med Virol. 1979;3:177-88.

(9.) Moser MR, Bender TR, Margolis HS, Noble GR, Kendal AP, Ritter DG. An outbreak of influenza aboard a commercial airliner. Am J Epidemiol. 1979;110:1-6.

(10.) McLean RL. Discussion after paper: the mechanism of spread of Asian influenza. Am Rev Respir Dis. 1961;83:36-8.

Address for correspondence: Raymond Tellier, Division of Microbiology, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8; email: raymond.tellier@ siekkids.ca

Camille Lemieux, * Gabrielle Brankston, * (1) Leah Gitterman, * Zahir Hirji, * and Michael Gardam * [dagger] * University Health Network, Toronto, Ontario, Canada; and [dagger] University of Toronto, Toronto, Ontario, Canada

Address for correspondence: Camille Lemieux, 200 Elizabeth St, NCSB 12C-1262, Toronto General Hospital, Toronto, Ontario, Canada, M5G 2C4; email: [e-mail]